Dry powder formulation comprising a corticosteroid and a beta-adrenergic for administration by inhalation

ABSTRACT

Compositions comprising a corticosteroid and a beta-adrenergic are useful for treating inflammatory or obstructive airways diseases.

TECHNICAL FIELD

The present invention relates to formulations for administration byinhalation by means of dry powder inhalers.

In particular, the invention relates to a dry powder formulationcomprising a corticosteroid and a beta₂-adrenergic drug in combination,its process of preparation, and therapeutic uses thereof.

BACKGROUND OF THE INVENTION

Active substances commonly delivered by inhalation includebronchodilators such as beta-2 adrenoreceptor agonists andanticholinergics, corticosteroids, anti-allergies and other activeingredients that may be efficiently administered by inhalation, thusincreasing the therapeutic index and reducing side effects of the activematerial.

Formoterol, i. e. 2′-hydroxy-5′-[(RS)-1-hydroxy-2{[(RS)-p-methoxy-α-methylphenethyl] amino} ethyl] formanilide,particularly its fumarate salt (hereinafter indicated as FF), is a wellknown beta-2 adrenergic receptor agonist, currently used clinically inthe treatment of bronchial asthma, chronic obstructive pulmonary disease(COPD) and related disorders.

Beclometasone dipropionate (BDP) is a potent anti-inflammatory steroid,named(8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-[2-(propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-ylpropionate, available under a wide number of brands for the prophylaxisand/or treatment of inflammatory respiratory disorders.

A formulation for pressurized metered dose inhalers (pMDIs) containingboth active ingredients in combination, both dissolved in a mixture ofHFA134a and ethanol as co-solvent is currently on the market. It hasbeen quoted in the literature as FF/BDP extra-fine formulation.

Said formulation provides a high lung deposition and uniformdistribution throughout the bronchial tree, and is characterized by thefact that is capable of delivering a high fraction of particles having adiameter equal or less than 1.1 micron. In particular, upon actuation ofthe inhaler, it gives rise to a respirable fraction of about 40% and afraction of particles having a diameter equal or less than 1.1 micron ofabout 12% for both active ingredients.

The major advantage of said formulation is related to the improvedpenetration into the bronchiole-alveolar distal part of the respiratorytree wherein inflammation is known to play a role in spontaneousexacerbations of asthma symptoms and wherein it is known that thedensity of the beta-2 adrenergic receptors is particularly high.

However, despite their popularity, pMDI formulation may have somedisadvantages in particular in elderly and pediatric patients, mostlydue to their difficulty to synchronize actuation from the device withinspiration.

Dry powder inhalers (DPIs) constitute a valid alternative to MDIs forthe administration of drugs to airways.

On the other hand, drugs intended for inhalation as dry powders shouldbe used in the form of micronised particles. Their volumetriccontribution could represent an obstacle to design a formulationtherapeutically equivalent to one wherein the drugs are delivered inform of liquid droplets.

WO 01/78693 discloses a dry powder formulation comprising formoterol andBDP in combination as active ingredient and, as a carrier, a fraction ofcoarse particles and a fraction made of fine excipient particles andmagnesium stearate.

Upon its actuation, the respirable fraction of BDP is about 40%, whilethat of formoterol is about 47%.

More recently Mariotti et al (European Respiratory Society AnnualCongress held in Amsterdam on Sep. 24-28, 2011), presented data about aFF/BDP dry powder formulation having a respirable fraction of about 70%for both active ingredients.

It is therefore an object of the invention to provide a powderformulation for DPIs comprising formoterol fumarate and BDP incombination, overcoming the problems indicated above and in particularto provide a powder formulation having therapeutic characteristicsmatching those of the corresponding pMDI formulation in form ofsolution.

The problem is solved by the formulation of the present invention.

SUMMARY OF THE INVENTION

The invention is directed to a dry powder formulation for use in a drypowder inhaler (DPI) comprising:

-   -   a) a fraction of fine particles made of a mixture composed of 90        to 99.5 percent by weight of particles of a physiologically        acceptable excipient and 0.5 to 10 percent by weight of        magnesium stearate, said mixture having a mass median diameter        lower than 20 micron;    -   b) a fraction of coarse particles constituted of a        physiologically acceptable excipient having a mass median        diameter equal to or higher than 100 micron, wherein the ratio        between the fine particles and the coarse particles being        between 1:99 and 30:70 percent by weight; and    -   c) formoterol fumarate dihydrate in combination with        beclometasone dipropionate (BDP) as active ingredient both in        form of micronized particles; wherein i) no more than 10% of        said BDP particles have a diameter lower than 0.6 micron, ii) no        more than 50% of said particles have a diameter comprised        between 1.5 micron and 2.0 micron; and iii) at least 90% of said        particles have a diameter lower than 4.7 micron.

In a second aspect, the invention is directed to a process for preparingthe dry powder formulation of the invention comprising the step ofmixing the carrier particles with the active ingredients.

In a third aspect, the invention concerns a dry powder inhaler filledwith the above dry powder formulation.

In a fourth aspect, the invention refers to the claimed formulation foruse in the prevention and/or treatment of an inflammatory or obstructiveairways disease such as asthma or chronic obstructive pulmonary disease(COPD).

In a fifth aspect, the invention refers to a method of preventing and/ortreating an inflammatory or obstructive airways disease such as asthmaor chronic obstructive pulmonary disease (COPD), which comprisesadministering by inhalation an effective amount of the formulation ofthe invention.

In a sixth aspect, the invention refers to the use of the claimedformulation in the manufacture of a medicament for the prevention and/ortreatment of an inflammatory or obstructive airways disease such asasthma or chronic obstructive pulmonary disease (COPD).

Definitions

By the term “physiologically acceptable” it is meant a safepharmacologically-inert substance.

By “daily therapeutically effective dose” it is meant the quantity ofactive ingredient administered by inhalation upon actuation of theinhaler.

Said daily dose may be delivered in one or more actuations (shots orpuffs) of the inhaler.

By the term “fine particles” it is meant particles having a size up tofew tenths of microns.

By the term “micronized” it is meant a substance having a size of fewmicrons.

By the term “coarse” it is meant particles having a size of one or fewhundred microns.

In general terms, the particle size of particles is quantified bymeasuring a characteristic equivalent sphere diameter, known as volumediameter, by laser diffraction.

The particle size can also be quantified by measuring the mass diameterby means of suitable known instrument such as, for instance, the sieveanalyser.

The volume diameter (VD) is related to the mass diameter (MD) by thedensity of the particles (assuming a size independent density for theparticles).

In the present application, the particle size of the active ingredientsis expressed in terms of volume diameter, while that of the excipient isexpressed in terms of mass diameter.

The particles have a normal (Gaussian) distribution which is defined interms of the volume or mass median diameter (VMD or MMD) whichcorresponds to the volume or mass diameter of 50 percent by weight ofthe particles, and, optionally, in terms of volume or mass diameter of10% and 90% of the particles, respectively.

Another common approach to define the particle size distribution is tocite three values: i) the volume median diameter d(v,0.5) which is thevolume diameter where 50% of the distribution is above and 50% is below;ii) d(v,0.9), where 90% of the volume distribution is below this value;iii) d(v,0.1), where 10% of the volume distribution is below this value.The span is the width of the distribution based on the 10%, 50% and 90%quantile and is calculated according to the formula.

${Span} = \frac{{D\left\lbrack {v,0.9} \right\rbrack} - {D\left\lbrack {v,0.1} \right\rbrack}}{D\left\lbrack {v,0.5} \right\rbrack}$

Upon aerosolisation, the particle size is expressed as mass aerodynamicdiameter (MAD) and the particle size distribution as mass medianaerodynamic diameter (MMAD). The MAD indicates the capability of theparticles of being transported suspended in an air stream. The MMADcorresponds to the mass aerodynamic diameter of 50 percent by weight ofthe particles.

The term “hard pellets” refers to spherical or semispherical units whosecore is made of coarse excipient particles.

The term “spheronisation” refers to the process of rounding off of theparticles which occurs during the treatment.

The term “good flowability” refers to a formulation that is easy handledduring the manufacturing process and is able to ensure an accurate andreproducible delivering of the therapeutically effective dose.

Flow characteristics can be evaluated by different tests such as angleof repose, Carr's index, Hausner ratio or flow rate through an orifice.

In the context of the present application the flow properties weretested by measuring the flow rate through an orifice according to themethod described in the European Pharmacopeia (Eur. Ph.) 7.3, 7^(th)Edition.

The expression “good homogeneity” refers to a formulation wherein, uponmixing, the uniformity of distribution of the active ingredient,expressed as coefficient of variation (CV) also known as relativestandard deviation (RSD), is less than 2.5%, preferably equal to or lessthan 1.5%.

The expression “respirable fraction” refers to an index of thepercentage of active particles which would reach the deep lungs in apatient.

The respirable fraction, also termed fine particle fraction (FPF), isevaluated using a suitable in vitro apparatus such as Andersen CascadeImpactor (ACI), Multi Stage Liquid Impinger (MLSI) or Next GenerationImpactor (NGI), preferably by ACI, according to procedures reported incommon Pharmacopoeias, in particular in the European Pharmacopeia (Eur.Ph.) 7.3, 7^(th) Edition.

It is calculated by the percentage ratio between the fine particle mass(formerly fine particle dose) and the delivered dose.

The delivered dose is calculated from the cumulative deposition in theapparatus, while the fine particle mass is calculated from thedeposition of particles having a diameter <5.0 micron.

The term “prevention” means an approach for reducing the risk of onsetof a disease.

The term “treatment” means an approach for obtaining beneficial ordesired results, including clinical results. Beneficial or desiredclinical results can include, but are not limited to, alleviation oramelioration of one or more symptoms or conditions, diminishment ofextent of disease, stabilized (i. e. not worsening) state of disease,preventing spread of disease, delay or slowing of disease progression,amelioration or palliation of the disease state, and remission (whetherpartial or total), whether detectable or undetectable. The term can alsomean prolonging survival as compared to expected survival if notreceiving treatment.

The term “coating” refers to the covering of the surface of theexcipient particles by forming a thin film of magnesium stearate aroundsaid particles.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a dry powder formulation for use in a drypowder inhaler (DPI) comprising a fraction of fine particles a), afraction of coarse particles b) and formoterol fumarate (FF) dihydratein combination with beclometasone dipropionate (BDP) as activeingredients, having the characteristics disclosed herein.

The fractions a) and b) constitute the “carrier” particles.

It has been surprisingly found that in order to obtain a FF/BDP drypowder formulation therapeutically equivalent to the corresponding pMDIformulation currently on the market, it is necessary to generate ahigher respirable fraction (FPF) as well as a higher fraction ofparticles having a diameter equal or less than 1.1 micron, for both theactive ingredients.

It has also been found that this can be achieved by strictly controllingthe particle size of the micronized BDP, and preferably its specificsurface area.

Unexpectedly, it has been indeed further found that by setting theparticle size distribution of BDP to the values herein claimed, not onlyits respirable fraction increases, but also that of formoterol fumarate(more than 60% vs about 47%).

Furthermore, the use of a micronized BDP characterized by such aselected, narrow, and well defined particle size distribution allows abetter reproducibility of its fine particle fraction (FPF) duringrepeated administration.

The formulation according to the invention also shows a good homogeneityof the active ingredients, a good flowability and adequate physical andchemical stability in the inhaler before use for pharmaceuticalpurposes.

Advantageously, the fine and coarse excipient particles may beconstituted of any physiologically acceptable material or combinationthereof; preferred excipients are those made of crystalline sugars, inparticular lactose; the most preferred are those made of α-lactosemonohydrate.

Preferably, the coarse excipient particles and the fine excipientparticles are both constituted of α-lactose monohydrate.

The fraction of fine particles a) must have a mass median diameter (MMD)lower than 20 micron, advantageously equal to or lower than 15 micron,preferably equal to lower than 10 micron, even more preferably equal toor lower than 6 micron.

Advantageously, the mass diameter of 90% of the fine particles a) islower than 35 micron, more advantageously lower than 25 micron,preferably lower than 15 micron, even more preferably lower than 10micron.

The ratio between the excipient particles and magnesium stearate withinthe fraction a) may vary depending on the doses of the activeingredients.

Advantageously, said fraction is composed of 90 to 99.5% by weight ofthe excipient and 0.5 to 10% by weight of magnesium stearate, preferablyof 95 to 99% of the excipient, and 1 to 5% of magnesium stearate. Apreferred ratio is 98% of the excipient and 2% of magnesium stearate.

Advantageously, at least 90% by weight of the particles of magnesiumstearate has a starting mass diameter of not more than 35 micron and aMMD of not more than 15 micron, preferably not more than 10 micron.

Advantageously, magnesium stearate may coat the surface of the excipientparticles in such a way that the extent of the surface coating is atleast of 5%, preferably more than 10%, more preferably more than 15%,even more preferably equal to or more than 35%.

When the excipient particles are made of lactose, the extent of surfacecoating, which indicates the percentage of the total surface of theexcipient particles coated by magnesium stearate, may be determined bywater contact angle measurement, and then by applying the equation knownin the literature as Cassie and Baxter, cited at page 338 of Colombo Iet al Il Farmaco 1984, 39(10), 328-341 and reported below.

cos ϑ_(mixture) =f _(MgSt) cos ϑ_(Mgst) +f _(lactose) cos ϑ_(lactose)

where f_(MgSt) and f_(lactose) are the surface area fractions ofmagnesium stearate and of lactose;

ϑ_(MgSt) is the water contact angle of magnesium stearate;

ϑ_(lactose) is the water contact angle of lactose

ϑ_(mixture) are the experimental contact angle values.

For the purpose of the invention, the contact angle may be determinedwith methods that are essentially based on a goniometric measurement.These imply the direct observation of the angle formed between the solidsubstrate and the liquid under testing. It is therefore quite simple tocarry out, being the only limitation related to possible bias stemmingfrom intra-operator variability. It should be, however, underlined thatthis drawback can be overcome by adoption of a fully automatedprocedure, such as a computer assisted image analysis. A particularlyuseful approach is the sessile or static drop method which is typicallycarried out by depositing a liquid drop onto the surface of the powderin form of disc obtained by compaction (compressed powder disc method).

The extent to which the magnesium stearate coats the surface of theexcipient particles may also be determined by scanning electronmicroscopy (SEM), a well known versatile analytical technique.

Such microscopy may be equipped with an EDX analyzer (an ElectronDispersive X-ray analyzer), that can produce an image selective tocertain types of atoms, for example magnesium atoms. In this manner itis possible to obtain a clear data set on the distribution of magnesiumstearate on the surface of the excipient particles.

SEM may alternatively be combined with IR or Raman spectroscopy fordetermining the extent of coating, according to known procedures.

Another analytical technique that may advantageously be used is X-rayphotoelectron spectroscopy (XPS), by which it has been possible tocalculate both the extent of coating and the depth of the magnesiumstearate film around the excipient particles.

The fraction of fine particles a) may be prepared according to one ofthe methods disclosed in WO 01/78693. Preferably, it could be preparedby co-micronization, more preferably using a ball mill. In some cases,co-milling for at least two hours may be found advantageous, although itwill be appreciated that the time of treatment will generally depend onthe starting particle size of the excipient particles and the desiredsize reduction to be obtained.

In a preferred embodiment of the invention the particles areco-micronised starting from excipient particles having a mass diameterless than 250 micron and magnesium stearate particles having a massdiameter less than 35 micron using a jet mill, preferably in inertatmosphere, for example under nitrogen.

As an example, alpha-lactose monohydrate commercially available such asMeggle D 30 or Spherolac 100 (Meggle, Wasserburg, Germany) could be usedas starting excipient.

Optionally, the fraction of fine particles a) may be subjected to aconditioning step according to the conditions disclosed in the pendingapplication n. WO 2011/131663.

The coarse excipient particles of the fraction b) must have a MMD of atleast 100 micron, preferably greater than 125 micron, more preferablyequal to or greater than 150 micron, even more preferably equal to orgreater than 175 micron.

Advantageously, all the coarse particles have a mass diameter in therange 50-1000 micron, preferably comprised between 60 and 500 micron.

In certain embodiments of the invention, the mass diameter of saidcoarse particles might be comprised between 80 and 200 micron,preferably between 90 and 150 micron, while in another embodiment, themass diameter might be comprised between 200 and 400 micron, preferablybetween 210 and 355 micron.

In a preferred embodiment of the invention, the mass diameter of thecoarse particles is comprised between 210 and 355 micron.

In general, the person skilled in the art shall select the most propersize of the coarse excipient particles by sieving, using a properclassifier.

When the mass diameter of the coarse particles is comprised between 200and 400 micron, the coarse excipient particles preferably have arelatively highly fissured surface, that is, on which there are cleftsand valleys and other recessed regions, referred to herein collectivelyas fissures. The “relatively highly fissured” coarse particles can bedefined in terms of fissure index or rugosity coefficient as describedin WO 01/78695 and WO 01/78693, incorporated herein by reference, andthey can be characterized according to the description therein reported.Said coarse particles may also be characterized in terms of tappeddensity or total intrusion volume measured as reported in WO 01/78695,whose teaching is incorporated herein by reference.

The tapped density of said coarse particles is advantageously less than0.8 g/cm³, preferably between 0.8 and 0.5 g/cm³. The total intrusionvolume is of at least 0.8 cm³ preferably at least 0.9 cm³.

The ratio between the fraction of fine particles a) and the fraction ofcoarse particles b) is comprised between 1:99 and 30:70% by weight,preferably between 2:98 and 20:80% by weight. In a preferred embodiment,the ratio is comprised between 10:90 and 15:85% by weight, even morepreferably is of 10:90 by weight.

The step of mixing the coarse excipient particles b) and the fineparticles a) is typically carried out in a suitable mixer, e.g. tumblermixers such as Turbula™, rotary mixers or instant mixer such as Diosna™for at least 5 minutes, preferably for at least 30 minutes, morepreferably for at least two hours. In a general way, the person skilledin the art shall adjust the time of mixing and the speed of rotation ofthe mixer to obtain a homogenous mixture.

When spheronized coarse excipient particles are desired in order toobtain hard-pellets according to the definition reported above, the stepof mixing shall be typically carried out for at least four hours.

All the micronized particles of beclometasone dipropionate (BDP) arecharacterized by a selected, narrow, and well defined particle sizedistribution in such a way that: i) no more than 10% of said particleshave a diameter lower than 0.6 micron, preferably equal to or lower than0.7 micron ii) no more than 50% of said particles have a diametercomprised between 1.5 micron and 2.0 micron, preferably between 1.6 and1.9 micron; and iii) at least 90% of said particles have a diameterequal to or lower than 4.7 micron, preferably equal to or lower than 4.0micron, more preferably equal to or lower than 3.8 micron.

The particular size distribution of BDP is characterized by: a d(v0.1)comprised between 0.8 and 1.0 micron, preferably between 0.85 and 0.95micron; a d(v0.5) comprised between 1.5 and 2.0 micron preferablybetween 1.6 and 1.9 micron, a d(v0.9) comprised between 2.5 and 4.7micron, preferably between 3.0 and 4.0 micron.

However the width of the particle size distribution of said BDPparticles, expressed as a span, should be comprised between 1.2 and 2.2,preferably between 1.3 and 2.1, more preferably between 1.6 and 2.0,according the Chew et al J Pharm Pharmaceut Sci 2002, 5, 162-168, thespan corresponds to [d(v,0.9)−d(v,0.1)]/d(v,0.5).

Advantageously, at least 99% of said particles [d(v,0.99)] have adiameter equal to or lower than 6.0 micron, and substantially all theparticles have a volume diameter comprised between 6.0 and 0.4 micron,preferably between 5.5 and 0.45 micron.

The size of the particles active is determined by measuring thecharacteristic equivalent sphere diameter, known as volume diameter, bylaser diffraction. In the reported examples, the volume diameter hasbeen determined using a Malvern apparatus, However, other equivalentapparatus may be used by the skilled person in the art.

Advantageously, the micronized particles of BDP have also a specificsurface area comprised between 5.5 and 7.0 m²/g, preferably between 5.9and 6.8 m²/g. The Specific Surface Area is determined byBrunauer-Emmett-Teller (BET) nitrogen adsorption method according to aprocedure known in the art.

All the micronized particles of formoterol fumarate dihydrate may have adiameter of less than 10 micron, preferably less than 6 micron.Advantageously at least 90% of the particles have a volume diameterlower than 5.0 micron. In a particular embodiment, the particle sizedistribution is such that: i) no more than 10% of the particles have avolume diameter lower than 0.8 micron, ii) no more than 50% of particleshave a volume diameter lower than 1.7 micron; and iii) at least 90% ofthe particles have a volume diameter lower than 5.0 micron. Micronisedformoterol fumarate dihydrate utilised in the formulation of theinvention is also advantageously characterized by a Specific SurfaceArea comprised between 5 and 7.5 m²/g, preferably between 5.2. and 6.5m²/g, more preferably between 5.5 and 5.8 m²/g.

Both the micronised active ingredients utilized in the formulation ofthe invention may be prepared by grinding in a suitable mill. Preferablythey are prepared by grinding using a conventional fluid energy millsuch as commercially available jet mill micronizers having grindingchambers of different diameters. Depending on the type of the apparatusand size of the batch, the person skilled in the art shall suitablyadjust the milling parameters such as the operating pressure, thefeeding rate and other operating conditions to achieve the desiredparticle size.

In particular, to achieve the claimed particle size distribution of BDP,it is highly advantageous to utilize a jet mill micronizer having agrinding chamber of a diameter of 300 mm.

In a preferred embodiment, the invention is directed dry powderformulation for use in a dry powder inhaler (DPI) comprising:

a) a fraction of fine particles made of a mixture composed of 98 percentby weight of particles of alpha-lactose monohydrate and 2 percent byweight of magnesium stearate, said mixture having a mass median diameterequal to or lower than 6 micron;

b) a fraction of coarse particles constituted of alpha-lactosemonohydrate having a mass diameter comprised between 212 and 355 micronand the ratio between the fine particles and the coarse particles being10:90 percent by weight; and

c) formoterol fumarate dihydrate in combination with beclometasonedipropionate (BDP) as active ingredient both in form of micronizedparticles; wherein i) no more than 10% of said BDP particles have adiameter [d(v,0.1)] lower than 0.7 micron, ii) no more than 50% of saidparticles have a diameter [d(v,0.5)] comprised between 1.6 micron and1.9 micron; and iii) at least 90% of said particles have a diameterlower than 4.0 micron.

The present invention is also directed to a process for preparing thedry powder formulation disclosed herein comprising the step of mixingthe fraction of fine particles a), the fraction of coarse particles b)with both the micronised active ingredients.

The carrier particles comprising the fraction of fine particles and thefraction of coarse particles may be prepared by mixing in suitableapparatus known to the skilled person, for example a Turbula™ mixer. Thetwo fractions are preferably mixed in a Turbula™ mixer operating at arotation speed of 16 r.p.m. for a period comprised between 30 and 300minutes, preferably between 150 and 240 minutes.

The mixture of the carrier particles with the active ingredientparticles may be carried out by mixing the components in suitableapparatus known to the skilled person, such as Turbula™ mixer for aperiod sufficient to achieve the homogeneity of the active ingredient inthe final mixture, preferably comprised between 30 and 120 minutes, morepreferably between 45 and 100 minutes.

Optionally, in an alternative embodiment, one active ingredient is firstmixed with a portion of the carrier particles and the resulting blend isforced through a sieve, then, the further active ingredient and theremaining part of the carrier particles are blended with the sievedmixture; and finally the resulting mixture is sieved through a sieve,and mixed again.

The skilled person shall select the mesh size of the sieve depending onthe particle size of the coarse particles.

The ratio between the carrier particles and the active ingredients willdepend on the type of inhaler device used and the required dose.

Advantageously, the formulation of the invention may be suitable fordelivering a therapeutic amount of both active ingredients in one ormore actuations (shots or puffs) of the inhaler.

For example, the formulations will be suitable for delivering 6-12 μgformoterol (as fumarate dihydrate) per actuation, especially 6 μg or 12μg per actuation, and 50-200 μg beclometasone dipropionate peractuation, especially 50, 100 or 200 μg per actuation.

The daily therapeutically effective dose may vary from 6 μg to 24 μg forformoterol and from 50 μg to 800 μg for BDP.

The dry powder formulation of the invention may be utilized with any drypowder inhaler.

Dry powder inhalers (DPIs) can be divided into two basic types: i)single dose inhalers, for the administration of single subdivided dosesof the active compound; each single dose is usually filled in a capsule;

ii) multidose inhalers pre-loaded with quantities of active principlessufficient for longer treatment cycles.

Said dry powder formulation is particularly suitable for multidose DPIscomprising a reservoir from which individual therapeutic dosages can bewithdrawn on demand through actuation of the device, for example thatdescribed in WO 2004/012801. Other multi-dose devices that may be usedare for instance the DISKUS™ of GlaxoSmithKline, the TURBOHALER™ ofAstraZeneca, TWISTHALER™ of Schering and CLICKHALER™ of Innovata. Asmarketed examples of single-dose devices, there may be mentionedROTOHALER™ of GlaxoSmithKline and HANDIHALER™ of Boehringer Ingelheim.

In a preferred embodiment of the invention, the dry powder formulationis filled in the DPI disclosed in WO 2004/012801.

In case the ingress of moisture into the formulation is to be avoided,it may be desired to overwrap the DPI in a flexible package capable ofresisting moisture ingress such as that disclosed in EP 1760008.

Administration of the formulation of the invention may be indicated forthe prevention and/or treatment of a wide range of conditions includingrespiratory disorders such as chronic obstructive pulmonary disease(COPD) and asthma of all types and severity.

Other respiratory disorders characterized by obstruction of theperipheral airways as a result of inflammation and presence of mucussuch as chronic obstructive bronchiolitis, and chronic bronchitis mayalso benefit by this kind of formulation.

The invention is illustrated in details by the following examples.

EXAMPLES Example 1—Preparation of Different Batches of MicronisedParticles of Beclometasone Dipropionate

Different batches of beclometasone dipropionate were milled in a jetmill micronizer MC JETMILL® 300 (Jetpharma Sa, Switzerland) having agrinding chamber of a diameter of 300 mm.

The micronised batches were characterised in terms of particle sizedistribution and Specific Surface Area.

The particle size was determined by laser diffraction using a Malvernapparatus. The parameter taken into consideration was the VD in micronof 10%, 50% and 90% of the particles expressed as d(v,0.1), d(v, 0.5)and d(v, 0.9), respectively, which correspond to the mass diameterassuming a size independent density for the particles. The span[d(v,0.9)−d(v,0.1)]/d(v,0.5) is also reported. The Specific Surface Area(SSA) was determined by BET nitrogen adsorption using a Coulter SA3100apparatus as a mean of three determinations.

The relevant data are reported in Table 1.

TABLE 1 Particle size distribution and Specific Surface Area (SSA) ofdifferent batches of micronised beclometasone dipropionate Particle size(μm) Batch 1 Batch 2 Batch 3 Batch 4 d (v, 0.1) 0.86 0.96 0.95 0.91 d(v, 0.5) 1.63 1.81 1.71 1.84 d (v, 0.9) 3.15 3.33 2.97 3.76 Span 1.411.31 1.19 1.54 SSA (m²/g) 6.61 5.90 6.12 6.28

Example 2—Preparation of the Fraction of Fine Particles a)

About 40 kg of co-micronised particles were prepared.

Particles of α-lactose monohydrate having a particle size of less than250 micron (Meggle D 30, Meggle), and magnesium stearate particleshaving a particle size of less than 35 micron in a ratio 98:2 percent byweight were co-micronised by milling in a jet mill operating undernitrogen to obtain the fraction of fine particles a).

At the end of the treatment, said co-micronized particles have a massmedian diameter (MMD) of about 6 micron.

Example 3—Preparation of the “Carrier” [Fraction a)+Fraction b)]

A sample of the fine particles of Example 1 were mixed with fissuredcoarse particles of α-lactose monohydrate having a mass diametercomprised between 212-355 micron, and obtained by sieving, in the ratio90:10 percent by weight.

The mixing was carried out in a Turbula mixer operating at a rotationspeed of 16 r.p.m. for a period of 240 minutes.

The resulting mixtures of particles, is termed hereinafter the“carrier”.

Example 4—Preparation of the Dry Powder Formulation

A portion of the “carrier” as obtained in Example 3 was mixed withmicronised formoterol fumarate dihydrate (FF) in a Turbula mixer for 30minutes at 32 r.p.m. and the resulting blend was forced through a sievewith mesh size of 0.3 mm (300 micron).

Micronised beclometasone dipropionate (BDP) batch 1 or 4 as obtained inExample 1 and the remaining part of the “carrier” were blended in aTurbula mixer for 60 minutes at 16 r.p.m. with the sieved mixture toobtain the final formulation.

The ratio of the active ingredients to 10 mg of the “carrier” is 6microg of FF dihydrate (theoretical delivered dose 4.5 microg) and 100microg of BDP.

The powder formulations were characterized in terms of aerosolperformances after loading it in the multidose dry powder inhalerdescribed in WO 2004/012801.

The evaluation of the aerosol performance was carried out using theAndersen Cascade Impactor (ACI) according to the conditions reported inthe European Pharmacopeia 6^(th) Ed 2008, par 2.9.18, pages 293-295.

After aerosolization of 3 doses, the ACI apparatus was disassembled andthe amounts of drug deposited in the stages were recovered by washingwith a solvent mixture and then quantified by High-Performance LiquidChromatography (HPLC). The following parameters, were calculated: i) thedelivered dose which is the amount of drug delivered from the devicerecovered in the impactor; ii) the fine particle mass (FPM) which is theamount of delivered dose having a particle size equal to or lower than5.0 micron; iii) the fine particle fraction (FPF) which is thepercentage of the fine particle dose; iv) the MMAD.

The results (mean value±S.D) are reported in Table 2.

TABLE 2 Aerosol performances Sample Batch 1 Batch 4 FF Delivered Dose[μg] 5.5 (±0.2) 5.1 (±0.3) Fine Particle Mass < 5 μm [μg] 3.4 (±0.3) 3.2(±0.2) Fine Particle Fraction < 5 μm [%] 62.8 (±2.4) 63.0 (±2.2) FineParticle Mass < 1 μm [μg] 0.9 (±0.1) 0.8 (±0.1) Fine Particle Fraction <1 μm [%] 16.9 (±1.0) 15.6 (±0.4) MMAD [μm] 1.69 (±0.0) 1.75 (±0.0) BDPDelivered Dose [μg] 89.8 (±3.7) 88.2 (±3.5) Fine Particle Mass [μg] 54.0(±4.0) 52.4 (±2.9) Fine Particle Fraction [%] 60.1 (±2.3) 59.4 (±1.8)Fine Particle Mass < 1 μm [μg] 24.2 (±2.5) 23.1 (±1.7) Fine ParticleFraction < 1 μm [%] 26.9 (±1.9) 26.2 (±1.2) MMAD [μm] 1.23 (±0.1)^(a)1.25 (±0.1)^(a) ^(a)GSD which is the geometric standard deviation

From the data of Table 2, it can be appreciated that the formulationsprepared using the micronized batches of BDP of Example 1 show a higherrespirable fraction (FPF), for both the active ingredients (slightlymore than 60%) than the corresponding pMDI formulation currently on themarket (about 40%).

They also give rise to a higher fraction of particles having a diameterequal or less than 1.1 micron (more than 25% for both the activeingredients).

Example 5—Therapeutic Equivalence of FF/BDP Dry Powder Formulation ofthe Invention with the Corresponding pMDI Formulation Currently on theMarket

The study was designed to show that FF/BDP dry powder formulationdelivered via the DPI disclosed in WO 2004/012801 is therapeuticallyequivalent to the corresponding pMDI formulation on the market.

Study Design:

A 5-way cross-over, double-blind, double-dummy clinical study.

69 asthmatic patients with FEV₁ 60% to 90% pred. were randomized. The 5single doses tested were: 24/400 μg FF/BDP via DPI or pMDI, 6/100 μgFF/BDP via DPI or pMDI and placebo.

Primary Objective:

FEV₁ AUC_(0-12h) which is the forced expiratory volume area under thecurve for the time period 0 to 12 hours.

FEV1 is the maximal amount of air that can be forcefully exhaled in onesecond.

Results

For FEV₁AUC_(0-12h), non-inferiority between formulations wasdemonstrated with low dose and with high dose.

Both doses were significantly better than placebo. Superiority of highdose versus low dose was shown for both formulations on FEV₁AUC_(0-12h),reaching statistical significance for DPI. Safety and tolerability weregood and comparable.

Example 6—Further Evidence of the Therapeutic Equivalence of FF/BDP DryPowder Formulation of the Invention with the Corresponding pMDIFormulation Currently on the Market

The aim of the study was to test the efficacy of 6/100 μg FF/BDP drypowder formulation delivered via the DPI (hereinafter FF/BDP DPI)disclosed in WO 2004/012801 versus the same dose of the correspondingpMDI formulation on the market (hereinafter FF/BDP pMDI) and the 100 μgBDP DPI formulation on the market (Clenil Pulvinal®, hereinafter BDPDPI).

Study Design:

A phase III, 8-week, multinational, multicentre, randomized,double-blind, triple-dummy, active controlled, 3-arm parallel-groupclinical trial was carried out in adult asthmatic patients.

One inhalation twice daily of each formulation was administered for onemonth of treatment.

Primary Objective:

To demonstrate that FF/BDP DPI is non-inferior to FF/BDP pMDI in termsof change from baseline to the entire treatment period in averagepre-dose morning peak expiratory flow (PEF).

PEF is a person's maximum speed of expiration, as measured with a peakflow meter, a small, hand-held device used to monitor a person's abilityto breathe out air. It measures the airflow through the bronchi and thusthe degree of obstruction in the airways.

Secondary Objectives:

To evaluate the superiority of FF/BDP DPI over BDP DPI in terms ofchange from baseline to the entire treatment period in average pre-dosemorning PEF;

To evaluate the effect of FF/BDP DPI on other lung function parametersand on clinical outcome measures, and the safety and tolerability.

Results:

The non-inferiority of FF/BDP DPI relative to FF/BDP pMDI in terms ofthe primary efficacy variable has been demonstrated.

The same results as for pre-dose morning PEF have been obtained forpre-dose evening PEF

No significant differences between treatments in terms of daily PEFvariability have been observed

The superiority over BDP DPI of both FF/BDP DPI and FF/BDP pMDI has alsobeen demonstrated.

The FF/BDP DPI formulation turned out to be comparable to FF/BDP pMDI interms of safety and tolerability.

1: A dry powder formulation for use in a dry powder inhaler (DPI)comprising: a) a fraction of fine particles made of a mixture composedof 90 to 99.5 percent by weight of particles of a physiologicallyacceptable excipient and 0.5 to 10 percent by weight of magnesiumstearate, said mixture having a mass median diameter lower than 20micron; b) a fraction of coarse particles constituted of aphysiologically acceptable excipient having a mass median diameter equalto or higher than 100 micron, wherein the ratio between the fineparticles and the coarse particles being between 1:99 and 30:70 percentby weight; and c) formoterol fumarate dihydrate in combination withbeclometasone dipropionate (BDP) as active ingredient both in form ofmicronized particles; wherein i) no more than 10% of said BDP particleshave a volume diameter lower than 0.6 micron, ii) no more than 50% ofsaid particles have a volume diameter comprised between 1.5 micron and2.0 micron; and iii) at least 90% of said particles have a volumediameter lower than 4.7 micron. 2: The formulation, according to claim 1wherein the d(v0.1) is comprised between 0.8 and 1.0 micron, the d(v0.5)is comprised between 1.5 and 2.0 micron, the a d(v0.9) is comprisedbetween 2.5 and 4.7 micron and the particle size span, defined as[d(v,0.9)−d(v,0.1)]/d(v,0.5) is comprised between 1.2 and 2.2. 3: Theformulation according to claim 2, wherein the BDP particles have aparticle size span comprised between 1.3 and 2.1. 4: The formulationaccording to claim 1, wherein the BDP particles are furthercharacterized by a specific surface area comprised between 5.5 and 7.0m²/g. 5: The formulation according to claim 4, wherein the specificsurface area is comprised between 5.9 and 6.8 m²/g. 6: The formulationaccording to claim 1, wherein the ratio of fine particles a) and coarseparticles b) is comprised between 2:98 and 20:80 percent by weight. 7:The formulation according to claim 6, wherein the ratio is 10:90 percentby weight. 8: The formulation according to claim 1, wherein the fractionof fine particles a) has a mass median diameter equal to or lower than10 micron. 9: The formulation according to claim 1, wherein the coarseparticles b) are made of alpha-lactose monohydrate. 10: The formulationaccording to claim 1, wherein the coarse particles b) have a mass mediandiameter equal to or greater than 175 micron. 11: The formulationaccording to claim 10, wherein the mass diameter is comprised between212 and 355 micron. 12: The formulation according to claim 1 constitutedof: a) a fraction of fine particles made of a mixture composed of 98percent by weight of particles of alpha-lactose monohydrate and 2percent by weight of magnesium stearate, said mixture having a massmedian diameter equal to or lower than 6 micron; b) a fraction of coarseparticles constituted of alpha-lactose monohydrate having a massdiameter comprised between 212 and 355 micron and the ratio between thefine particles and the coarse particles being 10:90 percent by weight;and c) formoterol fumarate dihydrate in combination with beclometasonedipropionate (BDP) as active ingredient both in form of micronizedparticles; wherein i) no more than 10% of said BDP particles have avolume diameter lower than 0.7 micron, ii) no more than 50% of saidparticles have a volume diameter comprised between 1.6 micron and 1.9micron; and iii) at least 90% of said particles have a volume diameterlower than 4.0 micron. 13: A dry powder inhaler filled with the drypowder formulation of claim
 1. 14: The formulation according to claim 1for use in the prevention and/or treatment of an inflammatory orobstructive airways disease. 15: The formulation according to claim 14,wherein the disease is asthma or chronic obstructive pulmonary disease(COPD).